U.S. Pat. No. 4,569,942 discloses certain 2-oxindole-1-carboxamides of the formula ##STR1## wherein, inter alia, X is H, fluoro, chloro, bromo, (C.sub.1 -C.sub.4)alkyl, (C.sub.3 -C.sub.7)cycloalkyl, (C.sub.1 C.sub.4)alkoxy, (C.sub.1 -C.sub.4)alkylthio, trifluoromethyl, (C.sub.1 C.sub.4)alkylsulfinyl, (C.sub.1 C.sub.4)alkylsulfonyl, nitro, phenyl, (C.sub.2 -C.sub.4)-alkanoyl, benzoyl, thenoyl, (C.sub.1 C.sub.4)alkanamido, benzamido or N,N-dialkylsulfamoyl having 1 to 3 carbons in each of said alkyls; Y is, H, fluoro, chloro, bromo, (C.sub.1 C.sub.4)alkyl, (C.sub.3 -C.sub.7)cycloalkyl, (C.sub.1 C.sub.4)alkoxy, (C.sub.1 C.sub.4)alkylthio and trifluoromethyl; R.sup.1 is (C.sub.1 -C.sub.6)-alkyl, (C.sub.3 -C.sub.7)cycloalkyl, (C cycloalkenyl, phenyl, substituted phenyl, phenylalkyl having 1 to 3 carbons in said alkyl, (substituted phenyl)alkyl having 1 to 3 carbons in said alkyl, (substituted phenoxy)alkyl having 1 to 3 carbons in said alkyl, (thiophenoxy)alkyl having 1 to 3 carbons in said alkyl, naphthyl, bicyclo-[2.2.1]heptan-2-yl, bicyclo[2.2.1]hept-5-en-2-yl or -- (CH.sub.2).sub.n --Q--R.degree.; n is zero, 1 or 2; Q is a divalent radical derived from furan, thiophene, pyrrole, pyrazole, imidazole, thiazole, isothiazole, oxazole, isoxazole, 1,2,3-thiadiazole, 1,3,4-thiadiazole, 1,2,5-thiadiazole, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran, tetrahydrothiopyran, pyridine, pyrimidine, pyrazine, benzo[b]furan and benzo[b]-thiophene; R.degree. is H or (C.sub.1 -C.sub.3)alkyl; and R.sup.2 is (C.sub.1 -C.sub.6)alkyl, (C.sub.3 -C.sub.7 )cycloalkyl, benzyl, furyl, thienyl, pyridyl or ##STR2## where R.sup.3 and R.sup.4 are each H, fluoro, chloro, (C.sub.1 C.sub.4)-alkyl, (C.sub.1 C.sub.4)alkoxy or trifluoromethyl.
That patent also discloses that said 2-oxinoole-1-carboxamides are inhibitors of cyclooxygenase and lipoxygenase, possess analgesic activity in mammals and are useful in treatment of pain and alleviation of symptoms of chronic diseases such as inflammation and pain associated with rheumatoid arthritis and osteoarthritis.
U.S. Pat. No. 4,556,672 discloses certain 3-acyl substituted-2-oxindole-1-carboxamides of the formula ##STR3## wherein X, Y and R.sup.1 are as described above for the compounds of U.S. Pat. No. 4,569,942. The compounds of U.S. Pat. No. 4,556,672 are disclosed as having the same activity as the compounds of U.S. Pat. No. 4,569,942 discussed above.
U.S. Pat. No. 4,861,794 discloses the use of compounds of the formula ##STR4## and the pharmaceutically-acceptable base salts thereof wherein X is H, Cl or F, Y is H or Cl and R is benzyl or thienyl to inhibit biosynthesis of interleukin-1 (IL-1) and to treat IL-1 mediated disorders and dysfunctions.
PCT patent application Ser. No. PCT/US88/03658, filed Oct. 18, 1988, describes non-steroidal antiinflammatory agents of the formula ##STR5## wherein each of X and Y is hydrogen, fluoro or chloro; R.sup.1 is 2-thienyl or benzyl; and R is alkanoyl, cycloalkylcarbonyl, phenylalkanoyl, benzoyl and certain substituted benzoyl groups, thenoyl, omega-alkoxycarbonylalkanoyl, alkoxycarbonyl, phenoxycarbonyl, 1-alkoxycarbonyloxy, alkylsulfonyl, methylphenylsulfonyl and dialkyl phosphonate.
U.S. application Ser. No. 07/473,266, filed Jan. 31, 1990, which is a continuation-in-part of U.S. application Ser. No. 07/340,113, filed Apr. 18, 1989 and assigned to the assignee hereof, describes novel 3-substituted-2-oxindole compounds of the formula ##STR6## and the pharmaceutically-acceptable salts thereof, wherein
X is H, F, Cl, Br, (C.sub.1 -C.sub.6)alkyl, (C.sub.3 -C.sub.8) )cyclo-alkyl, NO.sub.2, CF3, CN, SH, S(O).sub.m R.sup.3, OR.sup.4, COR.sup.4 or CONR.sup.4 R.sup.5 ;
Y is H, F, Cl, Br, (C.sub.1 -C.sub.6)alkyl, (C.sub.3 -C.sub.8)cyclo-alkyl, NO.sub.2, CF.sub.3, CN, SH, S(O).sub.q R.sup.17, OR.sup.18 or CONR.sup.18 R.sup.19 ;
R.sup.1 is H, alkanoyl of two to ten carbon atoms, cycloalkylcarbonyl of five to seven carbon atoms, phenylalkanoyl of seven to ten carbon atoms, chlorobenzoyl, methoxybenzoyl, thenoyl, omegaalkoxycarbonylalkanoyl, said alkoxy having one to three carbon atoms and said alkanoyl having three to five carbon atoms, alkoxy carbonyl of two to ten carbon atoms, phenoxycarbonyl, 1-(acyloxy)alkyl wherein acyl has one to four carbon atoms and said alkyl has two to four carbon atoms, 1-(alkoxycarbonyloxy)alkyl wherein said alkoxy has two to five carbon atoms and said alkyl has one to four carbon atoms, alkyl of one to three carbon atoms, alkylsulfonyl of one to three carbon atoms, methylphenylsulfonyl or dialkylphosphonate wherein each of said alkyl is one to three carbon atoms;
R.sup.2 is COR.sup.6, CONR.sup.7 R.sup.8, (C.sub.1 -C.sub.6)alkyl, (C.sub.3 -C.sub.8)cycloalkyl, phenyl or mono- or disubstituted phenyl wherein the substituent or substituents are each Cl, F, Br, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy or CF.sub.3 ;
Q is ##STR7##
A is H, F, Cl, Br, I, CF.sub.3, OR.sup.9, S(O.sub.p R.sup.10, COOR.sup.11, CONR.sup.9 R.sup.11, CN, NO.sub.2, COR.sup.10, CH.sub.2 OR.sup.11, OCOR.sup.10, NR.sup.9 R.sup.11, N(R.sup.9)COR.sup.11, SO.sub.2 NR.sup.9 R.sup.11, ##STR8##
B is H, F, Cl, Br, I, CF.sub.3, OR.sup.13, S(O).sub.t R.sup.14, COOR.sup.15, CONR.sup.13 R.sup.15, CN, NO.sub.2, COR.sup.14, CH.sub.2 OR.sup.15, OCOR.sup.14, NR.sup.13 R.sup.15, N(R.sup.13)COR.sup.15 or SO.sub.2 NR.sup.13 R.sup.15 ;
provided that A and B cannot both be H; or A and B are taken together, bonded to the same ring carbon of Q.sup.1 and equal oxo, or when A is not H, B is as defined above or (C.sub.1 -C.sub.4)alkyl;
A.sup.1 is F, Col, Br, I, CF.sub.3, OR.sup.9, S(O).sub.p R.sup.10, COOR.sup.11, CONR.sup.9 R.sup.11, CN, NO.sub.2, COR.sup.10, CH.sub.2 OR.sup.11, OCOR.sup.10, NR.sup.9 R.sup.11, N(R.sup.9)COR.sup.11 or SO.sub.2 NR.sup.9 R.sup.11 ;
Q.sup.1 is ##STR9## Q.sup.2 is
m, n, p, q and t are each zero, one or two;
W and Z are each O, S or NR.sup.11 ;
W.sup.1 and W.sup.2 are each O, S or NR.sup.10 provided that when one of W.sup.1 or W.sup.2 is O, S or NR.sup.10, the other is O or S;
R.sup.3, R.sup.6, R.sup.10, R.sup.14 and R.sup.17 are each (C.sub.1 -C.sub.6) alkyl or phenyl; R.sup.5, R.sup.8, R.sup.11, R.sup.15 and R.sup.19 are each H, (C.sub.1 -C.sub.6) alkyl or phenyl; R.sup.4, R.sup.7, R.sup.9, R.sup.13 and R.sup.18 are each H or (C.sub.1 -C.sub.6) alkyl; and R.sup.12 is H, F, Cl, Br, CF.sub.3 or (C.sub.1 -C.sub.6) alkyl. That application also describes inter alia a novel process which employs 1,1'-carbonyldiimidazole for preparing certain of the novel 3-substituted-2-oxindole compounds thereof.
Interleukin-1 (IL-1) has been reported to stimulate bone resorption both in vitro and in vivo. Hayward, M. and Fiedler-Nagy, Ch., Agents and Actions, 22, 251-254 (1987). It is also reported therein that IL-1, inter alia, induces the production of prostaglandin E.sub.2 (PGE.sub.2). PGE.sub.2 is a stimulator of bone resorption and has been implicated in bone loss. See Hayward, M. A. and Caggiano, T. J., Annual Reports in Medicinal Chemistry, 22, Sect. IV, Chapter 17, 169-178 (1987). Osteoporosis is defined as a debilitory loss of bone mineral which results in higher fracture rates. See Hayward, M. A. and Caggiano, T. J., supra, and references cited therein.
Interleukin-1 has been reported to be involved in the pathogenesis of many diseases See Dinarello, C. A., J. Clin. Immunol., 5, 287-297 (1985), the teachings of which are incorporated herein by reference. Further still, elevated levels of IL-1 like material have been found to be associated with psoriasis. Camp, R. D., et al., J. Immunol., 137, 3469-3474 (1986).